Researching Immunotherapy Side Effects to Improve Treatment

Cancer research and innovative treatments, like immunotherapy, are helping cancer patients with advanced disease live longer. 

“Immunotherapy is an entire new era in cancer treatment, one that we're very excited about,” says Kerry Reynolds, MD, a Mass General Cancer Center oncologist. “It’s designed to wake up the body's own immune system to attack cancer and control it over time.” 

Like chemotherapy and other cancer treatments, immunotherapy can have side effects – and in uncommon cases, they can be serious. The Severe Immunotherapy Complications (SIC) Service, co-directed by Dr. Reynolds and made up of more than 60 team members, is at the forefront of research and care for patients experiencing side effects from immunotherapy.  

Their recent study, published in Nature, uncovered valuable insights into an uncommon, yet dangerous heart inflammation side effect called myocarditis. Their findings are an exciting step toward doctors better managing immunotherapy side effects, so they can save even more lives with this novel treatment. 

What is immunotherapy for cancer? 

As the name suggests, immunotherapy uses the patient’s own immune system to fight cancer cells. 

“The immune system has two broad functions: it fights abnormal cells, like a disease or tumor cells, but it also protects us by helping us recover and heal from wounds,” explains Alexandra-Chloe Villani, PhD, a Mass General researcher who co-directs the SIC Service. “Cancer cells have learned how to co-op some of the mechanisms that tell our immune system when to stop fighting and instead start repairing a wound." 

Dr. Villani compares one of those protective mechanisms to brakes on a car. The brakes are called immune checkpoints and are designed to slow the immune system down, preventing it from going too far and attacking healthy cells. Cancer cells can escape the immune system by pretending to be a wound that needs repairing, so the brakes stop your immune system from attacking them. 

Some forms of immunotherapy, like immune checkpoint inhibitor (ICI) therapy, remove those brakes and encourage your immune system to continue fighting cancer cells. “The drug wakes up the immune system, and then the hope is that the immune system keeps the cancer in check,” Dr. Reynolds explains. 

Immune checkpoint inhibitor therapy was first approved for treating advanced-stage melanoma (skin cancer) in 2011. Now, the Food and Drug Administration (FDA) has approved the use of ICIs to treat more than 20 types of cancer across over 109 indications — and at earlier stages. According to the National Cancer Institute (NCI), some cancers treated by immune checkpoint inhibitor therapy include: 

• Lung cancer
• Head and neck cancer
• Brain cancer
• Breast cancer
• Certain urologic cancers, like bladder, renal cell (kidney), or prostate cancer
• Certain gastrointestinal cancers, like esophageal, stomach, liver, or colorectal cancer
• Cervical cancer
• Hodgkin’s lymphoma

Side effects of immune checkpoint inhibitor therapy 

Immunotherapy activates your immune system to better fight cancer cells, but as a result, your immune system can sometimes also act against healthy cells. It may not recognize the difference between a tumor and your own normal tissue.  

This can cause side effects, which are often mild and can be treated without stopping your ICI. However, some patients develop more serious side effects. These vary depending on the type of ICI (such as drug target, combination, and dose), the type of cancer you have, and how healthy you are before treatment. 

Inflammation side effect of immunotherapy 

In uncommon cases, immunotherapy can cause one or more organs to become inflamed (called an immune-related adverse event, or irAE). This inflammation can happen in nearly any organ system, which is why the SIC Service involves doctors and researchers from many different specialties.  

The most common organs affected by an irAE include your: 

• Skin, where you may experience rashes, blisters, sores, or itchy skin
• Endocrine system, which includes the glands and organs in your body that produce hormones. Your symptoms depend on which areas are inflamed, but they may include headaches, fatigue, abdominal pain, nausea, or vomiting.
• Gastrointestinal system, which may cause abdominal pain or diarrhea 

“Not all patients experience side effects from immunotherapy,” Dr. Reynolds emphasizes. “Some may develop a single immune-related adverse event affecting just one organ, while others may experience multiple adverse events involving several organs.”  

It’s important to share any early symptoms with your doctor. You may not need to stop your immune checkpoint inhibitor treatment if you’re having side effects, so talk to your doctor about what symptoms to watch out for and let them know right away if you experience any. 

“Patients should be aware of these side effects and shouldn’t be afraid of sharing early symptoms with their care team,” says Dr. Villani. “Think of the inflammation as a bushfire—if not contained early, it can rapidly escalate to a blaze that’s difficult to control, requiring significant intervention to stop it. But if caught early, it’s much easier to manage and even reverse it with the right tools.” 

In about 1 in 100 patients, ICI therapy creates inflammation in the heart. This can cause serious complications and even death. The recent study from the SIC Service looked at patients with this uncommon heart inflammation, known as immune checkpoint inhibitor myocarditis. 

Though it’s an uncommon complication, Dr. Villani notes that approximately half of cancer patients are eligible to receive ICI therapies as a part of treatment or clinical trial. This translates to a large number of patients that could potentially be affected. 

Immune checkpoint inhibitor myocarditis

In the heart, this side effect is known as immune checkpoint inhibitor myocarditis, or irMyocarditis. Myocarditis in general refers to inflammation of the heart muscle, which weakens the heart and reduces its ability to pump blood to the rest of the body. 

Signs and symptoms of irMyocarditis can include:  

• Chest pain
• Fatigue
• Shortness of breath
• Muscle or bone pain 

“Myocarditis is seen in the general population in the setting of viruses. Some viruses actually go to the heart and can cause inflammation of the heart muscle. Most people who get myocarditis related to a virus do fine, even though it sounds scary,” explains Tomas Neilan, MD, MPH, a Mass General Brigham cardiologist. Dr. Neilan is a member of the SIC team and the director of the Cardio-Oncology Program at Mass General.  

For patients on immune checkpoint inhibitor therapy, irMyocarditis is an uncommon complication. “Usually the clinicians taking care of these patients look carefully for the development of this particular side effect. If you don’t diagnose it quickly, it can become even more serious,” Dr. Neilan says. irMyocarditis can lead to potentially fatal events like arrhythmia and heart failure.  

Research on immunotherapy side effects, including irMyocarditis 

Researchers in the SIC effort are looking for ways to better understand, diagnose, and treat complications from immunotherapy, including irMyocarditis. “Can we predict who’s at risk? Because that could change the way we manage care and prioritize patient diagnosis and treatment,” Dr. Villani explains.  

In their study in Nature, a research team including senior authors Drs. Villani, Reynolds, and Neilan collected heart, blood, and tumor samples from immunotherapy cancer patients at Mass General. The samples of 28 patients who had developed irMyocarditis were compared with a control group of 41 unaffected patients. A team in Dr. Villani’s lab used new cutting-edge genomics technology to study each patient’s samples at the cellular level. 

“The single-cell genomics technologies that we have at Mass General allow us to isolate individual cells from tissue and blood and profile their genomic content with high resolution one cell at a time. We can then reconstruct the cellular composition of blood and tissue in patients and controls, enabling us to infer not only which cells are present, but also whether each cell exhibits normal or pathogenic features,” says Dr. Villani.

The team found specific changes in the heart among the irMyocarditis patients. They also found factors in blood samples that could predict whether a patient’s irMyocarditis disease presentation would be fatal. Their research showed that the immune response in the heart was different than the immune response that targets the tumor.  

Drs. Villani, Reynolds, and Neilan with their teams are conducting further research that aims to find more targeted treatments. Ideally, patients would be able to receive treatment for their irMyocarditis while also continuing their current immune checkpoint inhibitor immunotherapy regimen. 

“If there are different things that the immune system is attacking, then you might be able to treat them differently. You could allow the immunotherapy to continue to work its magic on the cancer, but actually fix the heart inflammation at the same time,” Dr. Neilan confirms.  

While further research is needed in a larger group of patients, the researchers are excited by the findings. “The results from our study give so much hope,” says Dr. Villani. “We learned so much about what key biological players are likely driving the biology of the heart inflammation associated with the use of immunotherapy, which lays the path for follow-up research. Such critical achievements were only possible because of the generosity of these patients and the amazing multidisciplinary team we have.”